Oral treatments for fungal infections of the skin of the foot (Review)

Transcription

1 Cochrane Database of Systematic Reviews Oral treatments for fungal infections of the skin of the foot (Review) Bell-Syer SEM, Khan SM, Torgerson DJ Bell-Syer SEM, Khan SM, Torgerson DJ. Oral treatments for fungal infections of the skin of the foot. Cochrane Database of Systematic Reviews 2012, Issue 10. Art. No.: CD DOI: / CD pub2. Oral treatments for fungal infections of the skin of the foot(review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley& Sons, Ltd.

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Antifungal versus placebo, Outcome 1 Cured (terbinafine 250 mg/day versus placebo).. 45 Analysis 1.2. Comparison 1 Antifungal versus placebo, Outcome 2 Cured (itraconazole 400 mg/day versus placebo). 46 Analysis 2.1. Comparison 2 Different types of antifungals, Outcome 1 Cured (terbinafine 250 mg/day versus itraconazole 100 mg/day) Analysis 2.2. Comparison 2 Different types of antifungals, Outcome 2 Cured (itraconazole 100 mg/day versus fluconazole 50 mg/day) Analysis 2.3. Comparison 2 Different types of antifungals, Outcome 3 Cured (fluconazole 50 mg/day versus ketoconazole 200 mg/day) Analysis 2.4. Comparison 2 Different types of antifungals, Outcome 4 Cured (ketaconazole 200 mg/day versus griseofulvin 1000 mg/day) Analysis 2.5. Comparison 2 Different types of antifungals, Outcome 5 Cured (terbinafine 250 mg versus griseofulvin 500 mg) Analysis 2.6. Comparison 2 Different types of antifungals, Outcome 6 Cured (fluconazole 150 mg/week versus fluconazole 50 mg/day) Analysis 2.7. Comparison 2 Different types of antifungals, Outcome 7 Cured (terbinafine 250 mg/2 weeks versus terbinafine 250 mg/4 weeks) Analysis 3.1. Comparison 3 Presentation of tinea pedis, Outcome 1 Plantar tinea pedis Analysis 3.2. Comparison 3 Presentation of tinea pedis, Outcome 2 Mixed distribution of tinea pedis APPENDICES FEEDBACK WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT DIFFERENCES BETWEEN PROTOCOL AND REVIEW NOTES INDEX TERMS i

3 [Intervention Review] Oral treatments for fungal infections of the skin of the foot Sally EM Bell-Syer 1, Sameena M Khan 1, David J Torgerson 1 1 Department of Health Sciences, University of York, York, UK Contact address: Sally EM Bell-Syer, Department of Health Sciences, University of York, Area 2 Seebohm Rowntree Building, Heslington, York, North Yorkshire, YO10 5DD, UK. sally.bell-syer@york.ac.uk. Editorial group: Cochrane Skin Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 10, Review content assessed as up-to-date: 24 July Citation: Bell-Syer SEM, Khan SM, Torgerson DJ. Oral treatments for fungal infections of the skin of the foot. Cochrane Database of Systematic Reviews 2012, Issue 10. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T About 15% of the world population have fungal infections of the feet (tinea pedis or athlete s foot). There are many clinical presentations of tinea pedis, and most commonly, tinea pedis is seen between the toes (interdigital) and on the soles, heels, and sides of the foot (plantar). Plantar tinea pedis is known as moccasin foot. Once acquired, the infection can spread to other sites including the nails, which can be a source of re-infection. Oral therapy is usually used for chronic conditions or when topical treatment has failed. Objectives To assess the effects of oral treatments for fungal infections of the skin of the foot (tinea pedis). Search methods For this update we searched the following databases to July 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 1946), EMBASE (from 1974), and CINAHL (from 1981). We checked the bibliographies of retrieved trials for further references to relevant trials, and we searched online trials registers. Selection criteria Randomised controlled trials of oral treatments in participants who have a clinically diagnosed tinea pedis, confirmed by microscopy and growth of dermatophytes (fungi) in culture. Data collection and analysis Two review authors independently undertook study selection, Risk of bias assessment, and data extraction. Main results We included 15 trials, involving 1438 participants. The 2 trials (71 participants) comparing terbinafine and griseofulvin produced a pooled risk ratio (RR) of 2.26 (95% confidence interval (CI) 1.49 to 3.44) in favour of terbinafine s ability to cure infection. No significant difference was detected between terbinafine and itraconazole, fluconazole and itraconazole, fluconazole and ketoconazole, or between griseofulvin and ketoconazole, although the trials were generally small. Two trials showed that terbinafine and itraconazole were effective compared with placebo: terbinafine (31 participants, RR 24.54, 95% CI 1.57 to ) and itraconazole (72 participants, RR 6.67, 95% CI 2.17 to 20.48). All drugs reported adverse effects, with gastrointestinal effects most commonly reported. Ten of the trials were published over 15 years ago, and this is reflected by the poor reporting of information from which to make a clear Risk of bias assessment. Only one trial was at low risk of bias overall. The majority of the remaining trials were judged as unclear risk of bias 1

4 because of the lack of clear statements with respect to methods of generating the randomisation sequence and allocation concealment. More trials achieved blinding of participants and personnel than blinding of the outcome assessors, which was again poorly reported. Authors conclusions The evidence suggests that terbinafine is more effective than griseofulvin, and terbinafine and itraconazole are more effective than no treatment. In order to produce more reliable data, a rigorous evaluation of different drug therapies needs to be undertaken with larger sample sizes to ensure they are large enough to show any real difference when two treatments are being compared. It is also important to continue to follow up and collect data, preferably for six months after the end of the intervention period, to establish whether or not the infection recurred. P L A I N L A N G U A G E S U M M A R Y Oral antifungal drugs for treating athlete s foot (tinea pedis) Athlete s foot (tinea pedis) is a fungal infection of the feet that is easily spread and difficult to get rid of. This review compared different oral antifungal drugs (i.e. drugs taken by mouth), and it included 15 trials, involving 1438 participants. There are several different kinds of oral treatments, and the trials we found considered all the oral drugs used to treat athlete s foot. We found terbinafine and itraconazole to be more effective than placebo. And we found terbinafine to be more effective than griseofulvin. Griseofulvin is a treatment that was developed much earlier than the new treatments, such as terbinafine and itraconazole; these newer treatments tend to be most evaluated. Trials of other drugs were not large enough to show differences between them. All drugs had side-effects; gastrointestinal effects were the most common. In future clinical trials, larger numbers of participants are needed to test different treatments in order to produce more reliable data. Also, future research should consider the costs of the different treatment approaches. B A C K G R O U N D Description of the condition Biology Fungal infections of the foot are common in people of all ages and can either affect the skin (tinea pedis) or the toenails (onychomycosis). The tenacity and duration of the infection can differ depending on the site. The cause of the infection is most frequently a dermatophyte (fungus), which inhabits and destroys keratin (a protein found in the outer layer of the skin). Tinea pedis, which tends to be restricted to the horny epidermal layers of the skin, is commonly known as athlete s foot. It is contracted from infected skin fragments from other humans and, in some cases, animals (Brooks 1996). There are several clinical forms of tinea pedis, which can be easily confused with other non-infectious skin conditions, such as the following: interdigital tinea pedis, which is macerated and scaly in appearance and found mainly between the toes; plantar type tinea pedis (moccasin foot), which is fine, powdery scaling on a background of redness covering the skin of the soles, heels, and sides of the foot; and vesicular (bullous) type, an acute inflammatory condition, characterised by the formation of vesicles, pustules, or blisters. This can mimic foot dermatitis of various causes. The causative organisms (dermatophytes) are classified into three genera: Epidermophyton, Microsporum, and Trychophyton. For tinea pedis, the main agents are Trichophyton rubrum, Trichophyton interdigitale (mentagrophytes), and Epidermophyton floccosum. Roseeuw 1999 found Trichophyton rubrum and Trichophyton interdigitale (mentagrophytes) were the most common pathogens in his European survey. Prevalence Traditionally, prevalence studies of tinea pedis have been conducted in school children (English 1959; English 1961), sailors (Catterall 1975), and coal-miners (Gentles 1957). More recently, athletes and those frequenting public swimming baths or modern-day leisure centres have been studied. Gentles 1973 examined 2

5 a random sample of 10% of all bathers at a public swimming bath and found the overall prevalence of tinea pedis was 8.5%. The prevalence was higher in adults (17%) than in children (4%). Auger 1993 investigated marathon runners and found a prevalence of 22%, with higher prevalence rates reaching 42% in the older age group (over 46 years). There is often a discrepancy between the methods of diagnosing tinea pedis whether by symptom (clinical) or microbiological confirmation (culture). For example, Gentles 1957 found that 90% of the coal miners studied had abnormalities of the skin of the feet, but only 21% were proven to be infected. A recent study in Australia (Merlin 1999) found that the prevalence of culture-proven tinea pedis was 5% in children, increasing with age from 2% in 4 to 6 year-olds to 10% in 16 to 18 year-olds (Merlin 1999). The increase in popularity of waterbased leisure facilities prompted Detandt 1995 to compare the level of dermatophyte contamination on the floors of traditional swimming pools and subtropical swimming complexes. This study found that the floors of subtropical swimming complexes are more highly-contaminated with dermatophytes than the floors of traditional swimming pools. The study concluded that this was due to large visitor numbers, long opening hours, the complexity of construction, and choice of materials. There is a clear trend showing that tinea pedis increases in prevalence with age, and Auger 1993 reported that his survey of tinea pedis indicated that men are infected about four times as frequently as women. This trend was confirmed by the Achilles study (Roseeuw 1999), which found that nearly twice as many men as women had fungal infections. Description of the intervention Before the late 1950s, only topical drugs were available. Topical drugs are those that are applied as a cream, spray, or lotion on the surface of the skin. Griseofulvin, the first significant oral (drug taken by mouth) antifungal agent, became available in 1958, and there have been many advances since then (Gupta 1994a). Although widely-used, griseofulvin is only effective for dermatophyte infections, and it needs to be taken for long treatment periods. It is associated with relatively minor side-effects. The azole class of drugs, the broad spectrum antifungals, were developed next. However, the first azole, ketoconazole, has been associated with liver damage (although this appears to be an idiosyncratic reaction (Jones 1982)), and it is now less favoured as an oral therapy. The 1980s saw the introduction of itraconazole and fluconazole, which were thought to have increased potency, decreased toxicity, and a wider spectrum of action than earlier azoles (Gupta 1994b). Azoles are fungistatic (inhibit fungal growth) and inhibit fungal cell development at a later stage. Terbinafine, an allylamine, was also introduced. This drug has a broad spectrum of antifungal activity and is fungicidal in its action, i.e. it destroys the fungal cell at a much earlier stage in its development than the azoles. Another less recognised oral treatment is bovine lactoferrin. Bovine lactoferrin (formerly known as lactotransferrin) is an iron-binding glycoprotein found in the secretions of some glands. It can be extracted from cow s milk. Because there is an increase in concentrations of lactoferrin at sites of infection during the inflammatory response, it is thought that lactoferrin is able to keep the iron bound, thus, preventing its use for bacterial proliferation (Alderova 2008). Lactoferrin and lactoferricin have been shown to inhibit in vitro growth of Trichophyton mentagrophytes, which is a dermatophyte responsible for skin conditions such as tinea pedis and ringworm (Wakabayashi 2000). How the intervention might work The numerous antifungal products available to treat tinea pedis differ both in costs and length of treatment. They can be taken as tablets (oral) or applied to the skin (topical). Clinical trials have focused mostly on topical treatments; oral therapy is more usually reserved for topical treatment failures and chronic conditions. Oral antifungal therapies are only available on prescription whereas many topical treatments are available to purchase overthe-counter (OTC). Topical therapies have usually been the firstline treatment for tinea pedis. A systematic review by Hart 1999 examined all topical therapies for tinea pedis and found that there were no significant differences in effectiveness between individual allylamines or individual azoles. It found that topical allylamines, which are available only on prescription, cured slightly more infections of tinea pedis than topical azoles or undecanoic acid, both of which are available OTC. The Hart 1999 review concluded that for tinea pedis the initial line of treatment should be with azoles or undecanoic acid, and allylamines should be reserved for topical treatment failures. However, tinea pedis can be resistant to treatment (Brautigam 1995), and topical treatments can be messy to apply and rely on the person complying with the recommended regimen. The ideal oral antifungal compound for the treatment of fungal infection should be fungicidal so that the treatment can be of short duration, should give high cure rates, minimise relapses, be easy for people to take, and have minimal adverse side-effects. Why it is important to do this review Tinea pedis is not a minor condition that will resolve if left alone or treated inadequately. Fungal infections are treated by dermatologists, general practitioners, and podiatrists. They are overwhelmed with large amounts of information, and a systematic review of the research evidence is needed. To date, the research evidence has not been systematically appraised and synthesised to answer the key questions set out below. This systematic review addressed the main research question as to whether or not there is an effective 3

6 oral treatment for tinea pedis and, if so, which treatment is most effective. Further research questions were as follows: Is there an optimum treatment duration? Is there an optimum dosage? Which intervention has fewest side-effects? Does any one clinical type of tinea pedis respond better to a particular treatment? O B J E C T I V E S To assess the effects of oral treatments for fungal infections of the skin of the foot (tinea pedis). M E T H O D S Secondary outcomes 1. Clinical assessment of signs, such as redness, scaling, pustules, and symptoms, such as itching, burning, and soreness. 2. Measurement of any recurrence of the condition after achieving a cure 12 weeks after the start of the intervention. 3. Side-effects of the treatments as measured by the frequency of reported adverse events. 4. Cosmetic acceptability of the end result to the participant, absence of itchiness, and discomfort. 5. Identification of the type of infecting dermatophytes at baseline and at final outcome assessment. Search methods for identification of studies We aimed to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress). Criteria for considering studies for this review Types of studies Randomised controlled trials (RCTs) of oral treatments for tinea pedis. Types of participants People, of any age, who have a fungal infection of the skin of the foot (tinea pedis) that has been clinically diagnosed and confirmed by microscopy and growth of dermatophytes in culture. Electronic searches For this update, we revised the search strategies for the five databases listed below, and we searched up to 24 July 2012: the Cochrane Skin Group Specialised Register using the search strategy in Appendix 1; the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library using the search strategy in Appendix 2; MEDLINE (from 1946) using the strategy in Appendix 3; EMBASE (from 1974) using the strategy in Appendix 4; and CINAHL via EBSCO (Cumulative Index to Nursing and Allied Health Literature, from 1981) using the strategy in Appendix 5. Types of interventions Any treatment administered orally that aims to treat the fungal infection. Types of outcome measures Primary outcomes 1. Mycological cure, as demonstrated by negative results on microscopy and no growth of dermatophyte in culture. This outcome is recognised as the most effective way of assessing if the fungal infection has been eradicated; evaluating the condition by its appearance alone is not reliable (Elewski 1996). Trials registries We searched the following trials registries on 23 July 2012 using the search terms tinea pedis and athletes foot : The metaregister of Controlled Trials ( The US National Institutes of Health Ongoing Trials Register ( The Australian New Zealand Clinical Trials Registry ( The World Health Organization International Clinical Trials Registry platform ( The EU Clinical Trials Register ( We have detailed the search activities we undertook for the original review but did not repeat for this update in Appendix 6. 4

7 Searching other resources We checked the reference lists of all retrieved trials for further references to relevant trials. We did not contact manufacturers again for this update because of time and resource constraints. Data collection and analysis Selection of studies Two review authors (SB-S, RH, or SK) independently assessed all citations and abstracts and categorised them into the following: clearly a RCT; possibly a RCT (abstract or title providing insufficient evidence to make a firm decision); or clearly not a RCT. We obtained all papers that were clearly or possibly a RCT in full text and further assessed them against the inclusion criteria, with any discrepancies being resolved by discussion. Data extraction and management We extracted and summarised details of the eligible trials using a data extraction sheet. Two review authors (SB-S, RH, or SK) extracted data independently and resolved disagreements by discussion. Where data were missing from reports, we attempted to contact the study authors to obtain the missing information. We included trials published in duplicate once, but extracted the maximal amount of data. We extracted the following data: country of origin; type of tinea pedis; unit of investigation (per participant) - site or foot or participant; care setting; number of participants randomised to each trial arm; eligibility criteria and key baseline participant data; details of the treatment regimen received by each group; details of any co-interventions; primary and secondary outcome(s) (with definitions); outcome data for primary and secondary outcomes (by group); duration of follow-up; number of withdrawals (by group); adverse events; and source of funding for trial. Assessment of risk of bias in included studies Two review authors (SB-S and SK) independently assessed each included study using The Cochrane Collaboration s tool for assessing risk of bias (Higgins 2011). This tool addresses six specific domains, namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other issues (e.g. extreme baseline imbalance) (see Appendix 7 for details of the criteria on which the judgement was based). We completed a Risk of bias table for each eligible study. We resolved disagreements about Risk of bias assessment by discussion. Where possible, where a lack of reported information resulted in an unclear decision, we contacted trial authors for clarification. We presented our assessment of the Risk of bias findings using a Risk of bias summary figure, which showed all of the judgements in a cross-tabulation of study by entry. This display of internal validity indicates the weight readers may give to the results of each study. We also aimed to present this assessment in the narrative of the review. We classified trials as being at high risk of bias if they were rated high for any one of three key criteria, i.e. randomisation sequence, allocation concealment, or blinded outcome assessment. Measures of treatment effect Where possible, we presented the outcome results for each trial with 95% confidence intervals (CI). We reported estimates for dichotomous outcomes as risk ratios (RR). We used the RR rather than odds ratio (OR) since ORs (when interpreted as RR) can give an inflated impression of the effect size when event rates are high, as is the case for many trials reporting healing of tinea pedis. Assessment of heterogeneity We considered trials that compared similar interventions for a meta-analysis. These trials were also subject to an assessment of statistical heterogeneity in order to decide whether to adopt a fixedeffect or random-effects model. A fixed-effect model is a mathematical model for combining the results of trials that assumes that the effect is truly constant in all the populations studied. Only variation within the study is taken to influence the uncertainty of results. A random-effects model is a mathematical model for combining the results of trials that allows for variation in the effect amongst the populations studied. Therefore, both within-study and between-study variations are included in the assessment of the uncertainty of results. Heterogeneity is caused by variability between trials in such areas as the type of participants, the length of treatment or follow up, dose or frequency of the intervention, quality of the trial, etc. We assessed statistical heterogeneity using the Chi² test (we considered a significance level of P < 0.1 to indicate heterogeneity) and the I² statistic estimate (Higgins 2003). The I² statistic estimate examines the percentage of total variation across trials due to heterogeneity rather than to chance. Values of I² statistic over 50% indicate a high level of heterogeneity. In the absence of clinical heterogeneity and in the presence of statistical heterogeneity (I² statistic over 50%), we used a random-effects model. Where there 5

8 was no clinical or statistical heterogeneity, we envisaged using a fixed-effect model. Data synthesis For each trial we calculated the cure rates (the primary outcome measure) at each outcome point from the reported mycological results. The longest available follow-up, within each trial, was generally used in summarising the overall effectiveness. We combined trials using a narrative overview with meta-analyses of outcome data where appropriate (in Review Manager 5). The decision to include trials in a meta-analysis depended on the availability of treatment effect data and assessment of heterogeneity. Individual trials with small sample sizes may not be able to estimate effects precisely. By combining the data from these trials a metaanalysis acquires the power to increase the precision of the estimate of effect. Subgroup analysis and investigation of heterogeneity We undertook a subgroup analysis of the clinical presentation of tinea pedis. We also investigated the sponsorship of trials by the pharmaceutical industry by noting all trials that had received sponsorship and whether the results of the study were in favour of the intervention manufactured by the sponsor. It is possible that publication bias exists by positive findings being preferably published by a pharmaceutical company (Begg 1989). R E S U L T S Nozickova 1998; Roberts 1987; Svejgaard 1998); and five trials were conducted in Asia (Hoharitanon 2005; Kim 1993; Voravutinon 1993; Widyanto 1993; Yamanchi 2000). All 15 trials used adult participants, with 1 study being conducted in a HIV population (27 participants) (Smith 2001). Elevan trials reported the clinical type of tinea pedis: 4 trials reported moccasin type tinea pedis; 3 trials, plantar type tinea pedis; and six trials reported either mixed presentations of tinea pedis along with tinea cruris and tinea corporis or simply reported tinea pedis with no further information. The sample size of trials ranged from 27 to 366, and the duration of follow up ranged from 2 to 16 weeks. This review evaluated six oral treatments: terbinafine, itraconazole, ketoconazole, fluconazole, griseofulvin, and bovine lactoferrin. Two trials compared active treatments (terbinafine, itraconazole) with placebo. One study compared different doses of the same drug (fluconazole); 1 study compared different brands of the same drug (itraconazole), and 11 trials evaluated head-to-head comparisons. Four trials reported receiving funding or support from pharmaceutical companies (DeKeyser 1994; Savin 1990a; Smith 2001; Svejgaard 1998). One study declared receiving medication from a pharmaceutical company (Roberts 1987); one study reported help from a pharmaceutical company, but did not specifically report funding (Hay 1995). One study had co-authors affiliated with a pharmaceutical company (Difonzo 1995). The pharmaceutical companies were Novartis (formerly Sandoz Pharmaceuticals) (terbinafine) and Janssen Pharmaceuticals, Inc. (itraconazole, ketoconazole). One study evaluating bovine lactoferrin, which is a cow s milk component, recruited employees from a Milk Company as participants (Yamanchi 2000). Description of studies We identified 42 trials; 15 met the inclusion criteria for the review; 25 were excluded; 1 study is awaiting assessment pending full text retrieval. In addition, we identified one potentially relevant study from a clinical trials registry; we contacted the study investigators who informed us that data are the property of the sponsoring pharmaceutical company. We contacted the company, but did not receive a reply. We put the information we have on this study in the Characteristics of ongoing studies tables. Included studies We identified 42 trials; 15 met the inclusion criteria for the review and evaluated 6 different treatments. All trials were in the English language. There were a total of 1438 participants in the included trials. The US was the country of setting for three trials (Savin 1990a; Savin 1990b; Smith 2001); seven trials were conducted in Europe (DeKeyser 1994; Difonzo 1995; Fischbein 1992; Hay 1995; Excluded studies Twenty-five trials (27 citations) did not meet the inclusion criteria (see the Characteristics of excluded studies tables). The main reasons for exclusion were as follows: Twelve did not present separate data for tinea pedis (Baldari 2000; Degreef 1987; Del Palacio 1993; Hay 1991; Jolly 1983; Lachapelle 1992; Schuller 1998; Stengel 1995; Tausch 1998; Van Hecke 1988; White 1991; Wishart 1994). Four were review articles (Bortolussi 2007; Bortolussi 2008; Humphreys 2004; Markova 2002). Three were not randomised trials (Decroix 2008; Gupta 1999; Yao 1999). Two reported data for systemic and topical therapy (Barnetson 1998; Lynfield 1974). Two did not perform microscopy and culture to obtain a diagnosis of fungal infection (Russell 1960; Won 1993). One reported topical therapy alone (Brugmans 1969). One reported insufficient data (Legendre 1980). We contacted all authors of excluded trials with a request for fur- 6

9 ther information. We received no response to enable any of these trials to be considered for inclusion in this review. Risk of bias in included studies Please see Figure 1 and Figure 2. 7

10 Figure 1. Risk of bias summary: review authors judgements about each Risk of bias item for each included study 8

11 Figure 2. Risk of bias graph: review authors judgements about each Risk of bias item presented as percentages across all included studies Allocation the allocation procedure, and we judged them to be at unclear risk of bias. Adequacy of randomisation process All included trials were described as randomised, but only one reported the method used to generate the randomisation sequence: This was the DeKeyser 1994 study, which used a computer-generated randomisation list. We judged this to be at low risk of bias for this domain. We judged two trials to be at high risk of bias: Hay 1995 numbered each participant who was then given a treatment box; it was thought this may have been similar to an alternate model, and Hoharitanon 2005 did not report the method of generating the randomisation sequence. Also, there was a notable difference observed in the size of each trial arm with no explanation. We judged the remaining 12 trials as at unclear risk of bias. Allocation concealment We judged four trials to be at low risk of bias for this domain; DeKeyser 1994 used numbered boxes containing study medication; Hoharitanon 2005 used opaque sachets containing medication; Roberts 1987 used a third party, the hospital pharmacy, to provide medication; and Yamanchi 2000 used a randomisation code to conceal allocation. The remaining 11 trials did not report Blinding Participants and personnel Eleven trials achieved participant blinding through the use of tablets or capsules of similar appearance. Although some of these trials did not explicitly state that the participants were blinded, they did report double-blinding, and then went on to describe the identical appearance of the medication. It was then judged to be a reasonable assumption that the participants were therefore likely blinded (DeKeyser 1994; Difonzo 1995; Fischbein 1992; Hay 1995; Hoharitanon 2005; Kim 1993; Roberts 1987; Savin 1990a; Savin 1990b; Widyanto 1993; Yamanchi 2000). Three trials were unclear in their reporting (Nozickova 1998; Svejgaard 1998; Voravutinon 1993), and one study (Smith 2001) was reported as open label and judged to be at high risk of bias. Treatment provider Two trials clearly achieved blinding of the treatment provider: Roberts 1987 used an independent third party to give the treat- 9

12 ment, and DeKeyser 1994 used identical treatment boxes independently prepared. The remaining 12 trials did not report on the blinding of the treatment provider. Although the trials were, in some cases, reported as double-blind, it was not explicit who was blinded. Therefore, we judged this domain to be at unclear risk of bias. One study was open-label; therefore, it was not blinded and thus at high risk of bias (Smith 2001). Outcome assessor We judged one study to be at low risk of bias because it was reported that the outcome assessment was based on mycological testing alone and was carried out by a laboratory remote from the trial site (DeKeyser 1994). Thirteen trials did not explicitly report on the blinding of the outcome assessor. Therefore, they were judged to be at unclear risk of bias. One study was an openlabel study (Smith 2001) and judged to be at high risk of bias. Effects of interventions Primary outcome - mycological cure Antifungal compared with placebo Two trials compared antifungal treatments with placebo: 1 trial of terbinafine (250 mg/day for 6 weeks) and 1 trial of itraconazole (400 mg/day for 1 week) with placebo both found that the antifungal treatment was statistically significantly better than placebo (Savin 1990a; Svejgaard 1998). Both trials also demonstrated that the cure rate continued to improve beyond the end of treatment. In the case of terbinafine, 65% of participants were cured 2 weeks after the end of the 6-week treatment period (RR 24.54, 95% CI 1.57 to ; Analysis 1.1). For itraconazole, 55% of participants were cured 8 weeks after the 1-week treatment period (RR 6.67, 95% CI 2.17 to 20.48; Analysis 1.2). Incomplete outcome data We judged six trials to be at low risk of bias; two trials reported no attrition (Roberts 1987; Yamanchi 2000); and four trials had either low rates of attrition (< 5%) or reported the number lost to follow up with reasons: This number was within reasonable limits (Difonzo 1995; Hoharitanon 2005; Savin 1990a; Voravutinon 1993). However, the remaining nine trials were judged to be at high risk of bias as they had either high rates of attrition (> 20%) or made no attempts to justify exclusion of data or to account for the losses. The highest rate of attrition was substantial and was reported by DeKeyser 1994 (68%). Selective reporting There was no evidence of selective reporting, and trials were judged to be at low risk of bias for this domain. It is noteworthy that study protocols were not sought. Other potential sources of bias One study had an imbalance in the baseline duration of fungal infection, with the group treated with terbinafine 250 mg/day for 2 weeks having a shorter duration of infection (151 +/- 163 weeks) compared with the group treated with terbinafine 250 mg/day for 4 weeks (376 +/- 468 weeks) (Smith 2001). We judged two trials to be at unclear risk of bias for this domain (Svejgaard 1998; Yamanchi 2000). The remaining trials appeared to be free from other potential sources of bias. The inclusion of tinea pedis caused by different fungal species (which was rarely reported on in the trials) was another potential source of bias in this field. Different types of antifungals Allylamines versus azoles Four trials compared terbinafine (250 mg/day for 2 weeks) and itraconazole (100 mg/day for either 2 weeks or 4 weeks) headto-head (DeKeyser 1994; Hay 1995; Kim 1993; Voravutinon 1993). Although 3 trials showed a higher cure rate for terbinafine, only 1 trial (DeKeyser 1994), which used itraconazole for 2 weeks, demonstrated a statistically significant difference in favour of terbinafine (RR 1.58, 95% CI 1.24 to 2.02; Analysis 2.1); terbinafine achieved a cure of 86% compared to itraconazole at 54%. Performing a meta-analysis (pooling of data from trials) achieves a more precise estimate of the treatment effect; however, the issue of heterogeneity is important. In considering clinical heterogeneity, the trials should look at a similar pool of participants, the same clinical condition, and have similar treatment periods and length of follow up. These issues are initially assessed visually by the researcher and then tested for statistical significance. As there was no evidence of heterogeneity (I² statistic = 0%) between the 3 trials with a common treatment length of 4 weeks, data for the final outcome measurements were pooled, using a fixed-effect model. This gave a risk ratio of 1.07 (95% CI 0.92 to 1.25; Analysis 2.1), which was not statistically significant. Azole versus azole Fluconazole (50 mg/day) was compared with 100 mg/day itraconazole (Difonzo 1995) and 200 mg/day ketoconazole (Fischbein 1992). Both trials demonstrated broadly similar cure rates of about 90% for all 3 drugs. There was no statistically significant difference 10

13 between fluconazole and itraconazole (RR 1.06, 95% CI 0.87 to 1.30; Analysis 2.2) nor was there any statistically significant difference between fluconazole and ketoconazole (RR 1.04, 95% CI 0.92 to 1.17; Analysis 2.3). However, as there were less than 30 evaluable participants in each intervention arm, the trials were not sufficiently powered to detect a significant difference. In addition, the trial data were poorly reported by Fischbein It was not clear if the unit of analysis was the individual participant or the infection site, and attempts to contact the trial authors to obtain clarification were unsuccessful. One study (Hoharitanon 2005) compared 3 different brands of itraconazole (200 mg/day for 2 weeks); 2 were generic brands and 1 was a new branded product. The study reported that there were cost implications, with the generic brands being cheaper. There were 133 evaluable participants, who were not allocated equally among the 3 arms. The trial reported that no statistically significant difference was detected between any of the groups (group 1: 11/ 18, group 2: 35/61, group 3: 27/54); these data were not plotted in a forest plot. It is worth noting that a cost analysis was not reported. Griseofulvin versus newer drugs One small trial compared griseofulvin (1000 mg/day) with ketoconazole (200 mg/day), both for 4 weeks of treatment, and no difference in cure rates was seen (Roberts 1987) (Analysis 2.4). The trial had a total of 29 participants, which raises the question of a type II error (not detecting a significant difference when there really is a difference of magnitude). Two small trials compared griseofulvin (500 mg/day) with terbinafine (250 mg/day) for either 4 (Widyanto 1993) or 6 weeks (Savin 1990b). Both trials showed that terbinafine had statistically significantly better cure rates, 100% and 86%, whereas griseofulvin achieved 50% and 33%. When the two trials were pooled, using a fixed-effect model (I² statistic = 0%), there was a statistically significant difference in favour of terbinafine (RR 2.26, 95% CI 1.49 to 3.44; Analysis 2.5). Different doses or length of treatment There has been only 1 trial comparing different doses, and it compared fluconazole 50 mg per day for a maximum of 6 weeks with fluconazole 150 mg once a week for a maximum of 6 weeks (Nozickova 1998). No statistically significant difference in cure rates was achieved (Analysis 2.6), but the trial was small (total n = 51). One study compared terbinafine 250 mg over 2 different treatment periods of 2 or 4 weeks in an open-label study. The study was small with 17 evaluable participants, all of whom were HIV positive. No significant difference was detected between the groups, with 50% (5/10) achieving a cure when treated with terbinafine for 2 weeks and 43% (3/7) achieving a cure when treated for 4 weeks (RR 1.17, 95% CI 0.41 to 3.36; Analysis 2.7) (Smith 2001). Bovine lactoferrin There has been 1 trial investigating bovine lactoferrin (LF) 600 mg and 2000 mg with placebo (Yamanchi 2000). There were a total of 37 participants with mild to moderate tinea pedis included in the study. No significance difference was reported between any of the groups. Results were presented in terms of dermatological improvement scores, with the proportion of cases showing marked improvement or improvement: 42.9% (6/14) in the group treated with 600 mg LF, 41.7% (5/12) in the group treated with 2000 mg LF, and 18.2% (2/11) in the placebo group. No mycological cure was achieved, and no adverse events were reported. Type of tinea pedis Terbinafine versus itraconazole Another source of heterogeneity considered was the type of tinea pedis. We used a random-effects model to pool the data for the two trials that studied only plantar tinea pedis (Hay 1995; Kim 1993) and for the two trials that did not differentiate between interdigital and plantar tinea pedis (DeKeyser 1994; Voravutinon 1993). No statistically significant difference was shown (Analysis 3.1; Analysis 3.2). Summary of results for mycological cure rates Terbinafine and itraconazole were more effective than no treatment (placebo). Terbinafine (two-weeks treatment) was more effective than itraconazole (two-weeks treatment). Terbinafine was more effective than griseofulvin. No significant difference in effectiveness was found between the following: two weeks of terbinafine versus four weeks of itraconazole; fluconazole versus either itraconazole or ketoconazole; griseofulvin and ketoconazole; different doses of fluconazole; different doses of terbinafine; different doses of bovine lactoferrin and placebo; or different brands of itraconazole but of the same dose. The type of tinea pedis does not appear to influence response to oral antifungal treatment, but this is based on sparse data. Secondary outcomes All trials reported secondary outcomes, but differed in the format of presentation and detail. 11

14 Clinical assessment We reported our secondary outcomes as an assessment of clinical signs and symptoms of the condition; these were exudation, erythema, scaling, vesiculation, pustules, crusting, desquamation, maceration, fissuring and pruritus, burning, rash, cellulitis, and pain. The trials assessed on average six different clinical signs and symptoms; most commonly, these were erythema, desquamation/ scaling, vesiculation, pustules, pruritus/itching, and maceration. This assessment was usually a subjective scoring system where the individual sign or symptom was rated as absent, mild, moderate, or severe, and given a score from 0 to 3. None of the trials reported that the outcome assessor was blind to treatment allocation. The trials presented the results in several different ways making it more difficult to make direct comparisons but allowing trends to be identified. Most trials calculated the mean clinical score across all assessed signs and symptoms at a stated point in time. In contrast, some trials presented results as a percentage of the population whose score was two or less for a total of all signs and symptoms. In general, the average clinical scores tended to reduce as the cure rate increased. Measurement of recurrence Further outcome measures were considered, namely the incidence of recurrence of the condition and maintenance of a cured condition 12 weeks after the start of treatment. Only 3 trials (Hay 1995; Roberts 1987; Savin 1990b) assessed the condition at 12 weeks or beyond. Roberts 1987 compared ketoconazole and griseofulvin and did not report the cure rate at 12 weeks, but found that the mean clinical score for signs and symptoms continued to improve in both groups. However, Hay 1995 demonstrated a continued improvement for participants treated with terbinafine at week 16, but in the itraconazole group, the infection had begun to reappear. Savin 1990b showed 6% recurrence with terbinafine and 25% recurrence with griseofulvin, but this was demonstrated in a study with very small sample sizes. Cosmetic acceptability No trialists reported the cosmetic acceptability of the end result or the amount of discomfort. Svejgaard 1998 included pain as a clinical symptom, and Difonzo 1995 mentioned subjective symptoms, but no detail was reported. Adverse events These were recorded in all but one trial (Roberts 1987). In general, all treatment regimens resulted in some adverse events. It was also noted that where trials had a placebo arm, these participants also reported adverse events. In all trials, the most frequently reported events were associated with the gastrointestinal system, such as diarrhoea and nausea, followed by headaches and the occurrence of skin complaints, such as rash, dermatitis, and pruritus. Less frequently reported adverse events were those associated with dizziness, taste disorders, and respiratory infections. Nobody suffered side-effects that led to any long-term or lasting damage. None of the participants who were treated with bovine lactoferrin reported adverse effects; however, haematological tests were significantly different to baseline in the group treated with 2000 mg. Please see Analysis 4.1 for a summary of adverse events reported for trials of tinea pedis. Identified fungi The analysis of identified dermatophytes showed Trichophyton rubrum to be the most prevalent infecting organism in the participants evaluated in 13 out of the 15 trials included in this review.trichophyton interdigitale (mentagrophytes) and Epidermophyton floccosum were also detected in these trials. Two trials included in this review reported Trichophyton mentagrophytes to be the most prevalent (Hoharitanon 2005; Widyanto 1993), and two trials (Smith 2001; Svejgaard 1998) did not report on infecting dermatophyte species. Although most trials identified the infecting species at baseline, none analysed the residual dermatophytes in individuals not cured. D I S C U S S I O N Tinea pedis is a common disease of the skin, and in the majority of cases, it is caused by a dermatophyte infection. A number of factors may have contributed to the growing incidence of this infection, including an aging population and increasing participation in fitness and leisure-related activities. In the UK, the National Health Service (NHS), the primary care team, and the affected individual make treatment decisions. One of the key decisions is the type of treatment, because antifungal drugs are available in either topical or oral form. Most topical treatments for tinea pedis are available over-the-counter and as such, are accessible for self-treatment, as well as being recommended by podiatrists and other healthcare professionals. Oral treatments are only available by prescription, and they are obtained through consultation with general practitioners, dermatologists, or nurse prescribers. Many of the advantages of oral treatment regimens are obvious; they are less time consuming and thought to have better compliance. It is recognised that oral treatments are best suited in the case of either topical treatment failures or more chronic presentations of tinea pedis. This systematic review addressed the main research question regarding whether or not there is an effective oral treatment for tinea pedis and, if so, which treatment is most effective. Further research questions were as follows: 12

15 Is there an optimum treatment duration? Is there an optimum dosage? Which intervention has fewest side-effects? Does any one clinical type of tinea pedis respond better to a particular treatment? We have tried to answer these questions in our summary of the results below. Summary of main results We included 15 RCTs in the review. Of the included trials, only 5 were published in recent years, with the other 10 trials having been published pre This is an indication that research into establishing the most effective oral treatment for tinea pedis does not attract a high level of current interest; another explanation may be publication bias. We considered trials that compared antifungal drugs with a placebo first as it is important to establish in the first instance whether a drug is actually effective when treating the target disease. There is evidence that both terbinafine and itraconazole are statistically significantly better than placebo. Is there an optimum dosage? The evidence from 1 small trial showed that terbinafine (250 mg) was statistically significantly better than itraconazole (100 mg) when given for 2 weeks. However, this trial result was based on a final evaluable sample of one third of the original number recruited to the trial. The trialists did not report the reasons for the loss to follow up. A pooled comparison of trials comparing terbinafine with four weeks of itraconazole showed no difference between the two treatments that reached significance. Two small trials comparing terbinafine (250 mg) with griseofulvin (500 mg) demonstrated significant evidence that terbinafine cures 52% more participants than griseofulvin. No difference was detected between ketoconazole and griseofulvin or between fluconazole and either ketoconazole or itraconazole. As only 106 participants took part in these 3 trials, however, there is a real danger of false negative findings. Similarly, the only dosefinding trial showed no significant difference between giving fluconazole for 50 mg a day or 150 mg a week. Does any one clinical type of tinea pedis respond better to a particular treatment? The two most common types of tinea pedis are plantar (side of the foot) and interdigital (between the toes). The type of tinea pedis was described in all trials except four, but no significant difference was demonstrated in the effectiveness of any one drug with respect to location. Therefore, there is no clear data that the type of tinea pedis is an important factor for the clinician when deciding on oral drug treatment. Is there an optimum treatment duration? With respect to length of treatment, terbinafine is routinely prescribed for 2 weeks (250 mg daily), and the most commonly evaluated regimen for itraconazole was 100 mg for 4 weeks. No trials investigated pulsing itraconazole, which gives 200 mg of itraconazole twice daily for only 7 days and is a regimen that is being introduced into clinical practice (MIMS 2000). In all trials, terbinafine was given at the recommended dose of 250 mg per day, but the treatment duration for terbinafine varied from 2 to 6 weeks in the trials, with the most frequent being 2 weeks. Terbinafine prescribed for 2 weeks at 250 mg daily may be the optimum treatment period and dosage. The effectiveness of oral antifungal drugs in treating secondary outcomes corresponded to their effectiveness in achieving primary outcomes. It appears that an antifungal drug s effectiveness in eradicating dermatophyte spores on the skin of the foot reflects the effectiveness of that drug in eradicating clinical signs and symptoms, such as scaling, pustules, itching, and burning. Which intervention has fewest side-effects? Twelve of the 15 included trials reported side-effects, with gastrointestinal effects being the most frequently reported. The lack of reported information about the types of dermatophytes surviving the treatment regimens evaluated in participants with positive culture at last outcome prevented us from making any conclusions about the sensitivity of different species to each individual drug therapy. The measurement of recurrence is important. There is little point in finding a drug treatment that achieves a good cure rate if the condition reappears some weeks after treatment has ended. The trials in this review were disappointing with respect to achieving good follow up, with only three trials assessing the condition beyond three months. Ideally, the condition should be re-assessed 6 to 12 months after treatment has ended, and if findings demonstrate a continuation of the cured condition, this reinforces the effectiveness of the treatment. Whilst it is recognised that a long follow up adds to the cost of a trial, it is important that the most effective treatments be those that not only achieve good cure rates but reduce relapse of the condition. Long follow-up periods also increase the possibility of losing trial participants; five trials included in this review reported a decrease in the number of participants evaluable from those originally recruited to the trials. Concern must be expressed at any missing data that is not accounted for. Of course there is an ongoing discussion of whether it is relapse or re-infection that causes the infection to reappear. In the case of tinea pedis, it is a condition that can coexist with a nail infection, and unless both are treated together, the nail might well prove a source of reinfection for the skin. Whether it is recurrence of the original condition or a re-infection, preventative measures should be considered. Routine oral treatments for prophylactic use cannot be justified due to possible side-effects, drug interactions, and high costs; however, topical agents are a realistic alternative. Hart